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postgraduate thesis: Molecular targeted therapies in advanced hepatocellular carcinoma

TitleMolecular targeted therapies in advanced hepatocellular carcinoma
Authors
Issue Date2012
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Yau, C. [邱宗祥]. (2012). Molecular targeted therapies in advanced hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4842114
AbstractWith the recent advances in the knowledge of hepato-carcinogenesis, there has been encouraging development in the molecular targeted therapy for patients with advanced hepatocellular carcinoma (HCC). Sorafenib, an anti-angiogenic multi-targeted receptor tyrosine kinase inhibitor, has become the standard of treatment in HCC patients with Child-Pugh A cirrhosis. Nevertheless, the benefits and safety profile of sorafenib in the majority of the unselected advanced HCC patients and other patient subgroups are still unclear. More importantly, the survival benefit associated with sorafenib use is generally modest in Asian population. Therefore, an unmet medical need remains for more effective therapeutic agents. This thesis studied the impact of molecular targeted therapy in the treatment of advanced HCC patients and it contains 10 original studies divided into six sections. The first section provides a concise overview of the epidemiology, risk factors, and current treatment options for HCC patients. Also, the molecular biology and opportunity for the use of targeted therapy in advanced HCC were discussed. The second section is about a new prognostic score system that we developed — Advanced Liver Cancer Prognostic System (ALCPS). Our study results showed that ALCPS was able to objectively estimate the 3-month survival probability of advanced HCC patients and thus could enhance patient selection for targeted therapy or clinical trials. The third section is about the use of sorafenib in the treatment of advanced HCC patients. The results of our single centre phase II study showed that sorafenib had good efficacy and acceptable tolerability in treating advanced HCC patients in hepatitis B endemic area. Furthermore, our retrospective study results confirmed that the overall survival benefits and overall treatment-related adverse events of sorafenib were comparable in elderly and young advanced HCC patients. More importantly, our other retrospective analysis showed that Child-Pugh (CP) A and CP B patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CP B patients, most benefits were observed in patients with score 7. Nevertheless, CP B patients were more susceptible to developing cirrhotic complications. Last but not least, our study also demonstrated that drop in serum alpha-fetoprotein level > 20% in the first 6 weeks of sorafenib treatment was a useful early surrogate endpoint for evaluating antitumor response and survival benefits. All these results are instrumental in guiding future rational use of sorafenib in advanced HCC population. The fourth section is about the role of targeted therapies in treating sorafenib-refractory advanced HCC patients. In a single arm phase II study, we showed that bevacizumab and erlotinib combination was not effective in treating advanced HCC patients who had failed prior sorafenib treatment. The fifth section of the thesis comprises results of four early phase novel clinical trials that may potentially improve the therapeutic outcomes in advanced HCC patients. First, our phase I/II study demonstrated that another anti-angiogenic agent — PTK787 had encouraging and possible synergistic activity when combined with intravenous doxorubicin in treating advanced HCC patients. Second, our multi-center phase II study results demonstrated promising activity with good tolerability of a novel combination — sorafenib together with capecitabine and oxaliplatin (SECOX) in the treatment of advanced HCC patients. Third, in a phase I study, we showed that pazopanib, a novel anti-angiogenic agent, had a manageable safety profile and preliminary activity in advanced HCC patients. Moreover, pazopanib reduced tumor vessel leakage, as shown by contrast-enhanced magnetic resonance imaging indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. Lastly, in another phase I study, we evaluated safety, pharmacological parameters, and potential antitumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. Our results illustrated that arginine depletion in humans can be achieved safely with peg-rhAgr1 in a dose-response manner and peg-rhArg1 had manageable safety profile and preliminary evidence of activity in advanced HCC patients. In the last section, the future perspectives about the use of molecular targeted therapy in the treatment of advanced HCC patients were discussed.
DegreeDoctor of Medicine
SubjectLiver - Cancer - Treatment.
Dept/ProgramMedicine

 

DC FieldValueLanguage
dc.contributor.authorYau, Chung-cheung.-
dc.contributor.author邱宗祥.-
dc.date.issued2012-
dc.identifier.citationYau, C. [邱宗祥]. (2012). Molecular targeted therapies in advanced hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4842114-
dc.description.abstractWith the recent advances in the knowledge of hepato-carcinogenesis, there has been encouraging development in the molecular targeted therapy for patients with advanced hepatocellular carcinoma (HCC). Sorafenib, an anti-angiogenic multi-targeted receptor tyrosine kinase inhibitor, has become the standard of treatment in HCC patients with Child-Pugh A cirrhosis. Nevertheless, the benefits and safety profile of sorafenib in the majority of the unselected advanced HCC patients and other patient subgroups are still unclear. More importantly, the survival benefit associated with sorafenib use is generally modest in Asian population. Therefore, an unmet medical need remains for more effective therapeutic agents. This thesis studied the impact of molecular targeted therapy in the treatment of advanced HCC patients and it contains 10 original studies divided into six sections. The first section provides a concise overview of the epidemiology, risk factors, and current treatment options for HCC patients. Also, the molecular biology and opportunity for the use of targeted therapy in advanced HCC were discussed. The second section is about a new prognostic score system that we developed — Advanced Liver Cancer Prognostic System (ALCPS). Our study results showed that ALCPS was able to objectively estimate the 3-month survival probability of advanced HCC patients and thus could enhance patient selection for targeted therapy or clinical trials. The third section is about the use of sorafenib in the treatment of advanced HCC patients. The results of our single centre phase II study showed that sorafenib had good efficacy and acceptable tolerability in treating advanced HCC patients in hepatitis B endemic area. Furthermore, our retrospective study results confirmed that the overall survival benefits and overall treatment-related adverse events of sorafenib were comparable in elderly and young advanced HCC patients. More importantly, our other retrospective analysis showed that Child-Pugh (CP) A and CP B patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CP B patients, most benefits were observed in patients with score 7. Nevertheless, CP B patients were more susceptible to developing cirrhotic complications. Last but not least, our study also demonstrated that drop in serum alpha-fetoprotein level > 20% in the first 6 weeks of sorafenib treatment was a useful early surrogate endpoint for evaluating antitumor response and survival benefits. All these results are instrumental in guiding future rational use of sorafenib in advanced HCC population. The fourth section is about the role of targeted therapies in treating sorafenib-refractory advanced HCC patients. In a single arm phase II study, we showed that bevacizumab and erlotinib combination was not effective in treating advanced HCC patients who had failed prior sorafenib treatment. The fifth section of the thesis comprises results of four early phase novel clinical trials that may potentially improve the therapeutic outcomes in advanced HCC patients. First, our phase I/II study demonstrated that another anti-angiogenic agent — PTK787 had encouraging and possible synergistic activity when combined with intravenous doxorubicin in treating advanced HCC patients. Second, our multi-center phase II study results demonstrated promising activity with good tolerability of a novel combination — sorafenib together with capecitabine and oxaliplatin (SECOX) in the treatment of advanced HCC patients. Third, in a phase I study, we showed that pazopanib, a novel anti-angiogenic agent, had a manageable safety profile and preliminary activity in advanced HCC patients. Moreover, pazopanib reduced tumor vessel leakage, as shown by contrast-enhanced magnetic resonance imaging indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. Lastly, in another phase I study, we evaluated safety, pharmacological parameters, and potential antitumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. Our results illustrated that arginine depletion in humans can be achieved safely with peg-rhAgr1 in a dose-response manner and peg-rhArg1 had manageable safety profile and preliminary evidence of activity in advanced HCC patients. In the last section, the future perspectives about the use of molecular targeted therapy in the treatment of advanced HCC patients were discussed.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.source.urihttp://hub.hku.hk/bib/B48421145-
dc.subject.lcshLiver - Cancer - Treatment.-
dc.titleMolecular targeted therapies in advanced hepatocellular carcinoma-
dc.typePG_Thesis-
dc.identifier.hkulb4842114-
dc.description.thesisnameDoctor of Medicine-
dc.description.thesislevelMaster-
dc.description.thesisdisciplineMedicine-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b4842114-
dc.date.hkucongregation2012-

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